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1、口服液態玻尿酸之臨床應用,前馬偕醫院神經科主治醫師仁欣診所院長蔡正浩,2023/2/23,玻尿酸的用途與困境口服玻尿酸的吸收皮膚領域退化性關節炎防老化的應用,2023/2/23,The repeat disaccharide of hyaluronan,-D-glucuronic acid-beta-1,3-N-acetylglucosamine-beta-1,4-(B),玻尿酸三維立體結構藍色帶代表親水部位,紅色帶代表疏水部位.呈白色，爲無定形固體，無臭無味，有強吸濕性，溶於水，不溶於有機溶劑。,玻尿酸分子化學結構與物理特性,2023/2/23,保水性:1公克的玻尿酸可以吸收500c.c.1
2、000c.c的水分，相當於5001000倍吸水能力,2023/2/23,玻尿酸的醫療用途,2023/2/23,目前玻尿酸在各種治療上的障礙,過去的經驗因分子量太大，口服、錠劑普遍效果不佳 只針對施打玻尿酸的位置，無法全面的保養皮膚 退化性關節炎（OA）玻尿酸進行關節腔注射：打會痛、打完尚有腫脹痛，病人看到針頭會怕 縫隙小，有傷到神經之危險，恐引起醫療糾紛 提前被代謝掉，健保給付有斷層很高比例的病人吃維骨力沒有效果,2023/2/23,有沒有其他有效安全的選擇?,如果玻尿酸可以改善吸收不良的問題以口服型式補充，而以內生性的方式達到需要之部位，那這種治療方式是否對某些病患來說是一個更好的選擇?!,
3、2023/2/23,玻尿酸的用途與困境口服玻尿酸的吸收皮膚領域退化性關節炎防老化的應用,2023/2/23,口服玻尿酸的吸收實驗一,在口服30分鐘後，即可在血液中偵測到,該報告證明口服玻尿酸可以順利被哺乳類吸收，堆積於血液，肌肉，硬骨組織，排出體外者僅小於5%This study examined the absorption,excretion and distribution of radiolabeled hyaluronan(HA)after a single oral administration in Wistar rats and Beagle dogs.To date its
4、therapeutic use has been limited to injections or topical applications,but there is no data on pharmacokinetics after oral intake.The gamma emitting isotope 99mtechnetium(Tc)was coupled to HA Less than 5%of the radioactivity appeared in feces after 72 hours in rats.Radioactivity was seen in blood,mu
5、scles,salivary glands and bone as early as 30 minutes,and peaked 4-6 hours in all non-alimentary tissues examined after oral administration.There were transient increases in radioactivity in shoulder joints and vertebrae 4 hours after oral administration of HA in both rats and Beagle dogs.Residence
6、time(t)in Beagle blood was 0.0134 hours.These results demonstrate that HA is absorbed and distributed to organs and joints after a single oral administration.,(FASEB,2004).A.G.Schauss,L.G.Balogh,A.G.Polyak,D.G.Mathe,R.G.Kiraly and G.G.Janoki American Institute for Biosocial and Medical Research,Inc
7、and National Institute for Health.,2023/2/23,日本的報告證明口服玻尿酸可以順利被哺乳類小腸絨毛吸收，在口服三小時內吸收比率高達80%以上，殘留於消化道之玻尿酸小於16%。,口服玻尿酸的吸收實驗二,2023/2/23,口服玻尿酸的吸收實驗三,Study on absorption of hyaluronic acid after an oral administration in rats2005年23期蒋秋燕,凌沛学,黄思玲,林洪,张天民,JIANG Qiu-yan,LING Pei-xue,HUANG Si-ling,LIN Hong,ZHANG
8、Tian-min 目的探讨透明质酸口服吸收的机制.方法采用放射免疫法测定大鼠单剂量口服透明质酸溶液和3种单糖(D-葡糖醛酸、N-乙酰氨基葡糖及两者等摩尔配比)溶液后血清中透明质酸的浓度,用梯形法计算AUC.结果生理盐水对照组和D-葡糖醛酸组的血清中透明质酸没有出现峰值;透明质酸组在口服后约2 h,出现明显的透明质酸吸收峰;另外两个单糖组在口服后7 h左右,出现一个明显的透明质酸合成峰.透明质酸组的AUC013 h为2 417ghL-1,实测max为187.6gL-1,tmax为2.0 h.结论透明质酸口服后可以被机体吸收,且能以非单糖的形式被机体吸收.,2023/2/23,口服玻尿酸只有少量會
9、被酵素分解成醣類及熱量，玻尿酸口服後在腸道的吸收率可以達到 7090%人體雙盲臨床實驗證實口服玻尿酸，4小時後血液中HA含量開始增加，12小時後達到最高峰比對照組高出 70倍，顯示口服玻尿酸的生理利用率及吸收率極佳連續服用28天後可以達到最穩定的濃度與代謝,HA 在人體的吸收研究,2023/2/23,口服玻尿酸之美國專利,United States Patent 6,924,273August 2,2005 Chondroprotective/restorative compositions and methods of use thereof AbstractThe instant inve
10、ntion provides a method of treating or preventing osteoarthritis,joint effusion,joint inflammation and pain,synovitis,lameness,post operative arthroscopic surgery,deterioration of proper joint function including joint mobility,the reduction or inhibition of metabolic activity of chondrocytes,the act
11、ivity of enzymes that degrade cartilage,the reduction or inhibition of the production of Hyaluronic acid,said method comprising orally administering to a mammalian species a therapeutically effective amount of Hyaluronic Acid or pharmaceutically acceptable salts thereof.Additionally,compositions con
12、taining hyaluronic acid;chondroitin sulfate,and glucosamine sulfate in a paste formulation are also disclosed which can be administered on their own or can be used as a feed additive.,2023/2/23,如果玻尿酸可口服吸收在皮膚美容上是否有幫助?!,2023/2/23,玻尿酸的用途與困境口服玻尿酸的吸收皮膚領域退化性關節炎防老化的應用,2023/2/23,玻尿酸在皮膚之作用,(1)表皮層epidermis(2)
13、真皮層dermis(3)玻尿酸HA(4)collagen膠原蛋白,玻尿酸流失後的肌膚會使真皮層的含水量降低，漸漸失去彈性與光澤，同時對陽光、環境的傷害，肌膚自我修護力也下降，進一步生成皺紋、黑斑等。,玻尿酸補充細胞間的基質與活性消除皺紋，軟化肌膚,2023/2/23,施打玻尿酸在皮膚之應用,Hyaluronic acid injection can be used to improve the skins contour and reduce depressions in the skin due to acne,scars,injury or lines.Immediately or wit
14、hin a few hours after injection the site may be red and swollen.This usually disappears within a week.Another one or two treatments(at least a week apart)may be necessary to achieve the desired correction.Hyaluronic acid implantation is not permanent.Like natural hyaluronic acid,manufactured hyaluro
15、nic acid once injected into the skin will gradually break down and be absorbed by the body.In most cases,the hyaluronic acid augmentation usually lasts between 6-9 months.Compared to collagen implants hyaluronic acid appears to have a longer augmentation effect,possibly lasting 2 to 3 times longer t
16、han the average collagen implant.To maintain the initial results,repeat hyluronic acid injections or top-up treatments will be necessary.Most people following this protocol have 2 to 3 treatments per year.,2023/2/23,以口服single dose的方式投與裸鼠，結果顯示玻尿酸在八小時之後就被傳送到全身，主要分布於皮膚當中，睪丸、關節，並可在體內持續72小時以上。細胞實驗的結果，玻尿酸
17、的濃度越高，細胞分化，進行吞噬作用、釋放發炎反應激素的效用也越大。顯示玻尿酸具有活化免疫系統的功能。玻尿酸以口服方式確實可被哺乳類吸收，再分布於特定部位發揮其功能。細胞實驗證實小分子玻尿酸可以調控免疫系統的活性,Data on file,VGH-TC,台灣 台中榮總 口服玻尿酸之研究,2023/2/23,餵食 螢光 HA 的動物試驗追蹤結果,照片左邊的為沒有餵食螢光HA的大白鼠（對照組），右邊的大白鼠為餵食0.5 mg螢光HA，經過48小時後的螢光偵測結果,照片左邊的為沒有餵食螢光HA的大白鼠（對照組），右邊的大白鼠為餵食0.5 mg螢光HA，經過72小時後的螢光偵測結果,Data on fi
18、le,VGH-TC,2023/2/23,玻尿酸與膠原蛋白,玻尿酸,在人體的組織內:膠原蛋白如同鋼筋玻尿酸如同水泥穩定組織架構維持細胞活性,膠原蛋白,玻尿酸在軟骨組織中的聚集作用,2023/2/23,玻尿酸幫助膠原蛋白合成之研究,Hyaluronic acid counteracts interleukin-1-induced inhibition of collagen biosynthesis in cultured human chondrocytes AbstractAlthough,hyaluronic acid(HA)is used in the treatment of osteo
19、arthritis for 30 years,the mechanism of its protective action on collagen metabolism disturbances in tissues during inflammation is not known.Therefore,the present study was undertaken to evaluate the mechanism of IL-1 action(inductor of experimental inflammation)on deregulation of collagen biosynth
20、esis in cultured human chondrocytes and the effect of HA on the process.It has been found that IL-1 strongly induced inhibition of collagen biosynthesis,while HA counteracted the process.The mechanism of this phenomenon was found at both transcriptional and post-transcriptional level.IL-1 was found
21、to down regulate the expression of mRNA for type II collagen and to inhibit prolidase activity,an enzyme that plays an important role in collagen biosynthesis at post-translational level.HA was shown to counteract the IL-1-dependent inhibition of both processes.During experimental inflammation of ch
22、ondrocytes cultured in 0.1%FBS there was no differences in the expression of 1-integrin independently of cell number and the presence of HA in growth medium.In chondrocytes cultured in 5%FBS,IL-1 up-regulated the expression of 1-integrin receptor while HA abolished the effect.The data suggest that H
23、A-dependent up-regulation of collagen biosynthesis in IL-1-treated chondrocytes may involve stimulation of prolidase activity in serum starved cells and may also originate at the transcriptional level in the cells cultured in standard conditions.Source/Source2006,vol.54,Pharmacological research ISSN
24、1043-6618,pp.275-2817 page(s)(article),2023/2/23,玻尿酸加速fibroblast之增生,Hyaluronan facilitates transforming growth factor-beta1-mediated fibroblast proliferation.This study aims to understand the role of the matrix polysaccharide hyaluronan(HA)in influencing fibroblast proliferation and thereby affectin
25、g wound healing outcomes.To determine mechanisms that underlie scarred versus scar-free healing,patient-matched dermal and oral mucosal fibroblasts were used as models of scarring and non-scarring fibroblast phenotypes.Specifically,differences in HA generation between these distinct fibroblast popul
26、ations have been examined and related to differences in transforming growth factor-beta(1)(TGF-beta(1)-dependent proliferative responses and Smad signaling.There was a differential growth response to TGF-beta(1),with it inducing proliferation in dermal fibroblasts but an anti-proliferative response
27、in oral fibroblasts.Both responses were Smad3-dependent.Furthermore,the two fibroblast populations also demonstrated differences in their HA regulation,with dermal fibroblasts generating increased levels of HA,compared with oral fibroblasts.Inhibition of HA synthesis in dermal fibroblasts was shown
28、to abrogate the TGF-beta(1)-mediated induction of proliferation.Inhibition of HA synthesis also led to an attenuation of Smad3 signaling in dermal fibroblasts.,J Biol Chem.2008 Mar 7;283(10):6530-45.Epub 2008 Jan 2.,2023/2/23,補充玻尿酸可多方保養肌膚,2023/2/23,如果玻尿酸可口服吸收在退化性關節炎是否有幫助?!,2023/2/23,玻尿酸的用途與困境口服玻尿酸的吸
29、收皮膚領域退化性關節炎防老化的應用,2023/2/23,退化性關節炎多發生於 45 歲以上的中老年人身上。根據統計，在台灣隨著年齡的增加，罹患退化性關節炎的比例隨之增加：,退化性關節炎(OA),2023/2/23,骨關節炎(Arthritis),軟骨裂解的產物會導致滑液囊的慢性發炎反應。滑液囊中的吞噬細胞產生細胞媒介物，包括 interleukin 1(IL-1)、tumor necrosis factor-alpha、metalloproteinase 會回到軟骨處，直接破壞組織或刺激軟骨細胞產生更多的metalloproteinase。最後，關節的結構遭受改變，為了穩定關節，便發生補償性的
30、硬骨增生,2023/2/23,骨關節發炎時相關之物質,2023/2/23,補充可使用之玻尿酸以恢復關節液的彈性和黏度。活化纖維母細胞之活性,使玻尿酸之合成再開始抑制發炎反應中IL-1的作用,使軟骨細胞及膠原蛋白維持增加減少OA 病人的疼痛感,治療退化性關節炎之策略,Osteoarthritis,2023/2/23,Osteoarthritis Treatment過去20年，內科醫生對骨關節炎病患的治療是採取直接注射 HA 至膝蓋的關節液，因為這些病患的身體中原本就存在骨關節處的 HA 較薄一層，當關節活動摩擦時會感疼痛，而額外補充注射 HA 能豐厚關節保護層，暫時抑制疼痛約幾天至幾星期，一些文
31、獻的研究目地皆是探討 HA 在這種醫療方式上扮演的角色 Sundblad L.Glycosaminoglycans and glycoproteins in synovial fluid.In:Balazs EA,Jeanloz RW,editors.The amino sugars.The chemistry and biology of compounds containing amino sugars,vol.IIA.New York:Academic Press 1965:229-50.Wobig M,Bach G,Beks P,Dickhut A,Runzheimer J,Schwi
32、eger G,et al.The role of elastoviscosity in the efficacy of viscosupplementation for osteoarthritis of the knee:a comparison of hylan G-F 20 and a lower-molecular-weight hyaluronan.Clin Ther 1999;21:1549-62.Weiss C,Balazs EA,St.Onge R,Denlinger JL.Clinical studies of the intraarticular injection of
33、HealonR(sodium hyaluronate)in the treatment of osteoarthritis of human knees.Osteoarthritis symposium.Palm Aire,Fla.,October 20-22,1980.Semin Arthritis Rheum.1981;11(suppl 1):143-4.,目前治療關節炎(OA)普遍的方式,2023/2/23,注射玻尿酸患者與注射placebo之比較 A controlled,randomized,double-blind,parallel-design multicentre study
34、 J.Karlsson,L.S.Sjgren1 and L.S.Lohmander2,2023/2/23,玻尿酸幫助膠原蛋白合成之研究,Hyaluronic acid counteracts interleukin-1-induced inhibition of collagen biosynthesis in cultured human chondrocytes AbstractAlthough,hyaluronic acid(HA)is used in the treatment of osteoarthritis for 30 years,the mechanism of its pr
35、otective action on collagen metabolism disturbances in tissues during inflammation is not known.Therefore,the present study was undertaken to evaluate the mechanism of IL-1 action(inductor of experimental inflammation)on deregulation of collagen biosynthesis in cultured human chondrocytes and the ef
36、fect of HA on the process.It has been found that IL-1 strongly induced inhibition of collagen biosynthesis,while HA counteracted the process.The mechanism of this phenomenon was found at both transcriptional and post-transcriptional level.IL-1 was found to down regulate the expression of mRNA for ty
37、pe II collagen and to inhibit prolidase activity,an enzyme that plays an important role in collagen biosynthesis at post-translational level.HA was shown to counteract the IL-1-dependent inhibition of both processes.During experimental inflammation of chondrocytes cultured in 0.1%FBS there was no di
38、fferences in the expression of 1-integrin independently of cell number and the presence of HA in growth medium.In chondrocytes cultured in 5%FBS,IL-1 up-regulated the expression of 1-integrin receptor while HA abolished the effect.The data suggest that HA-dependent up-regulation of collagen biosynth
39、esis in IL-1-treated chondrocytes may involve stimulation of prolidase activity in serum starved cells and may also originate at the transcriptional level in the cells cultured in standard conditions.Source/Source2006,vol.54,Pharmacological research ISSN1043-6618,pp.275-2817 page(s)(article),2023/2/
40、23,玻尿酸加速fibroblast之增生,Hyaluronan facilitates transforming growth factor-beta1-mediated fibroblast proliferation.This study aims to understand the role of the matrix polysaccharide hyaluronan(HA)in influencing fibroblast proliferation and thereby affecting wound healing outcomes.To determine mechanis
41、ms that underlie scarred versus scar-free healing,patient-matched dermal and oral mucosal fibroblasts were used as models of scarring and non-scarring fibroblast phenotypes.Specifically,differences in HA generation between these distinct fibroblast populations have been examined and related to diffe
42、rences in transforming growth factor-beta(1)(TGF-beta(1)-dependent proliferative responses and Smad signaling.There was a differential growth response to TGF-beta(1),with it inducing proliferation in dermal fibroblasts but an anti-proliferative response in oral fibroblasts.Both responses were Smad3-
43、dependent.Furthermore,the two fibroblast populations also demonstrated differences in their HA regulation,with dermal fibroblasts generating increased levels of HA,compared with oral fibroblasts.Inhibition of HA synthesis in dermal fibroblasts was shown to abrogate the TGF-beta(1)-mediated induction
44、 of proliferation.Inhibition of HA synthesis also led to an attenuation of Smad3 signaling in dermal fibroblasts.,J Biol Chem.2008 Mar 7;283(10):6530-45.Epub 2008 Jan 2.,2023/2/23,玻尿酸幫助軟骨細胞合成之研究,The effect of hyaluronic acid on IL-1-induced chondrocyte apoptosis in a rat model of osteoarthritis The
45、purpose of this article was to study the effect of hyaluronic acid(HA)on chondrocyte apoptosis in a rat osteoarthritis in vitro model(exposure to IL-1)and explore its mechanism.HA could inhibit IL-1-induced chondrocyte apoptosis in our cell culture model system.It was showed that addition of HA to t
46、he medium was able in a dose-dependent way to reduce the impairment of the mitochondrial membrane potential and to restore mitochondrial ATP production.This study shows that HA could suppress in a dose-dependent way chondrocyte apoptosis in our IL-1-induced osteoarthritis model.The suppression of in
47、flammatory cytokine activity within the joint might be one important mechanism of the clinical action of HA in the treatment of OA.2008 Orthopaedic Research Society.J Orthop Res,2023/2/23,2023/2/23,2023/2/23,OA Knee:excitability of nociceptors of articular nerves,nerve impulses&nerve sensitivity:hyp
48、eralgesic,spontaneously discharge,sensitive to non-noxious joint movementHA:decreased ongoing nerve activity&movement evoked nerve activity,nerve impulse decreased 60%of control,impulse discharge and firing frequency decreased to 65%and 45%of controlIon channels decreased mechanical sensitivityRat m
49、odel:abnormal gait:attenuation of prostaglandin E2,bradykinin synthesisDirect or indirect effects on substance P(excitatory amino acids,prostaglandins,NO),Hyaluronan and nociception,口服 玻尿酸之臨床有效性,Effect of a natural extract of chicken combs with a high content of hyaluronic acid(Hyal-JointR)on pain r
50、elief and quality of life in subjects with knee osteoarthritis:a pilot randomized double-blind placebo-controlled trialPublished:21 January 2008Nutrition Journal 2008,7:3 doi:10.1186/1475-2891-7-3Methods:Twenty subjects aged 40 years with knee osteoarthritis(pain for at least 15 days in the previous
